Globoid leukodystrophy (Krabbe's disease) is a sphingolipidosis that results from inherited deficiency of cerebroside Beta-galactosidase activity and perhaps deficiencies of other enzyme activities as well. The disease affects the central nevous system and peripheral nerves. To further our understanding of globoid leukodystrophy (GLD), a breeding colony will be maintained to produce naturally affected canine models of the disease. Canine GLD closely resembles human GLD. Affected dogs are ideal experimental models in which to test the efficacy of prophylactic and therapeutic measures. We will examine the therapeutic potential of kidney transplants as a means of supplying galactocerebrosidase to the enzymatically deficient GLD recipients. We expect to describe GLD pathogenesis morphologically in terms of transitions from normal white matter to the advacne degenerated state. Initially we shall concentrate on the ultrastructure of GLD neuropathy since this represents a simpler system than does the CNS. Neurilemma cell viability will be investigated by experimentally producing Wallerian degeneration in nerves of affected dogs. By quantifying both lesion distribution and neuron loss in the CNS and correlating the former with morphologic and biochemical regional features, we hope to explain lesion distribution in terms of GLD pathogenesis. Lesion distribution will be correlated also with the pattern of myelin development in Cairn Terrier dogs. In collaboration with Dr. Kunihiko Suzuki, we shall examine the nature and extent of the enzymatic disorder(s) in canine GLD. Enzymatic diagnoses of genotype will be confirmed by breeding trials and necropsies. By sacrificing litters from carrier parents neonatally, maturation of canine galactocerebrosidase activity will be determined per genotype and correlated with myelin development. Ultimately we hope to explain how deficient activity in certain enzymes leads to white matter degeneration, why certain regions are more susceptible than others, and what can be done to prevent development of the disease.